There is a rapidly expanding literature calling for the study of the role of gene- environment interactions (GWE) in modulating human functioning. According to Caspi &Moffitt (2006), "gene-environment interactions occur when the effect of exposure to an environmental pathogen on a person's health is conditional on his or her genotype" (p. 583). These GxE studies rely on the judicious choice of genes and variants within those genes, in combination with newer analytical approaches, and a thorough characterization of the environmental exposure. This approach has great potential for determining the complex sources of individual differences, particularly when confronting a common pathogen such as life stress;it is consistent with NIH's goal to discover pathways to prevention and individualized medicine. Recent research has revealed substantial interactions between biological and social factors as they relate to behavioral problems in children, including antisocial and violent behavior and PTSD. It is also well established that dysfunctional Hypothalamic-Pituitary Adrenal Axis (HPAA) response to stress (reflected in abnormal levels of stress-induced cortisol) predisposes to the development of mental health conditions and substance abuse. Our on-going study investigates how social-environmental exposures and selected biologicals, including the relationship between cortisol levels and resting heart rate, relate to a wide range of psychological outcomes. This revision seeks to extend these studies with new genetic studies that target known allelic variations in genes critically involved in modulating HPAA activity. These allelic variations are found in genes coding for glucocorticoid- and mineralocorticoid receptors, corticotropin-releasing hormone receptor 1, and FK506 binding protein 5, that are thought to either protect from or confer susceptibility to develop mental health conditions in response to stress exposure. Our ongoing study of children of women involved in the Criminal Justice system, a population living under extreme levels of stress, and their matched controls, provides an unparalleled opportunity to conduct a developmental study of GxE interactions that includes the role of known allelic variants of prominent candidate genes that modulate HPAA activity and associated psychiatric symptoms. PUBLIC HEALTH RELEVANCE: From a public health perspective, policy driven decisions regarding youth, especially those at elevated risk for untoward outcomes, must be based on sound scientific data. The goal of the proposed investigation is to advance our knowledge and understanding of the consequences of maternal involvement with the Criminal Justice System on the substance use/abuse/dependence and other psychopathology of their children through the use of genetic and other biological analyses.